Thrombopoietin (TPO) via its receptor, c-mpl, is the primary physiological regulatory of platelet production. Because of this role in controlling platelet production via the megakaryocytic lineage, the TPO/c-mpl ligand-receptor pair is thought to act in a "lineage dominant" fashion. Evidence from our group and others points to an expanded role for c-mpl and its ligand that includes the early stages of hematopoietic development. This expanded role for c-mpl/TPO in hematopoietic stem/progenitor cell function. An increased understanding of the role that c-mpl and its ligand play in stem/progenitor cell function could have a significant impact on bone marrow transplantation protocols used in the treatment of wide spectrum of human diseases. Recent work by our group demonstrates that c-mpl is expressed by a subset of cells enriched for primitive hematopoietic progenitor activity in both mouse and man. These findings suggest that in addition to its role in the biology of the megakaryocytic linages that c-mpl and its ligand also influences the biology of primitive hematopoietic stem/progenitor cells. We hypothesize that c-mpl expression demarcates a subset of CD34+CD38- cells capable of long-term lineages hematopoietic engraftment and self-renewal. In support of this hypothesis we have found that c-mpl is expressed by a subset of CD34+CD38- cells in adult bone marrow that can repopulate multiple lineages and CD34+ stem/progenitor cells in an in vivo assay for human hematopoiesis. To further test this hypothesis, we propose to define the developmental potential of CD34+CD38-mpl+ cells using in vivo assays for human hematopoiesis (SCID-hu Bone) and thymopoiesis (SCID-hu Thy/Liv) in immunodeficient mice. Specifically, we will: (1) Determine whether CD34+CD38-c-mpl+ cells are enriched for cells with long-term multi- lineage hematopoietic repopulating activity, (2) Determine whether CD34+CD38-c-mpl+ cells can develop into T-lymphoid cells and (3) Determine whether CD34+CD38-c-mpl+ cells have the capacity to self- renew.